Rivaroxaban is an oral anticoagulant. Rivaroxaban is a direct factor Xa inhibitor. It has been reported that rivaroxaban may replace warfarin in the treatment and prevention of strokes and heart attacks, with a market potential well over a billion USD per year. Accordingly, efficient, economical, and high yielding processes for preparing rivaroxaban are needed.
It has been discovered herein that rivaroxaban may be prepared directly via a 1,3-cycloaddition reaction, as described herein. However, the starting materials needed for such a process have been observed herein to be highly insoluble. Surprisingly, the quite insoluble starting materials are converted to intermediates under the solution-based reaction conditions described herein. Moreover, it has also been discovered herein that intermediates in the process for preparing rivaroxaban crystallize from the reaction mixture in highly purified form.
Described herein are efficient processes for the preparation of rivaroxaban and pharmaceutically acceptable salts thereof. In one embodiment, the processes described herein include the step of preparing the oxazolidinone present in rivaroxaban and pharmaceutically acceptable salts thereof from an oxirane and an isocyanate.
In one illustrative embodiment of the inventions described herein, the processes include the step of preparing 4-(4-morpholin-2-onyl)phenyl isocyanate from 4-(4-morpholin-2-onyl)aniline, or a salt thereof, and an acylating agent. In another embodiment, the processes include the step of preparing a compound of the formula
or a salt thereof from 4-(4-morpholin-2-onyl)phenyl isocyanate and an oxirane of the formula
where RA is halo or a protected amino group; and RB is halo, amino, or a protected amino group.
In another embodiment, the processes include the step of preparing a compound of the formula
or a salt thereof from
or a salt thereof, and an acylating agent.
In another embodiment, the processes include the step of preparing a compound of the formula
or a salt thereof from
or a salt thereof, and RCC(O)SH, where RC is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
In another embodiment, described herein are process that proceed in high overall yield. In another embodiment, described herein are process that require minimal purifications using chromatography, or alternatively, do not require any purifications using chromatography. In another embodiment, described herein are process where the products from each step are isolated as solids and/or crystalline solids. In another embodiment, described herein are process that proceed with high enantiomeric excess. It is to be understood that the processes described herein may be performed using racemic material and to produce racemic material, or using optically active material to produce optically active material of either absolute configuration. It is also to be understood that the processes described herein may be routinely adapted to prepare any of a wide variety of materials having a predetermined enanatiomeric excess or a predetermined range of enanatiomeric excess.